This application is for the continuation of support of a collaborative program with Dr. Wayne Bowen (NIH) and Dr. Michael Walker (Brown University) to develop sigma-1 and sigma-2 binding site selective ligands as biochemical probes to characterize their binding sites and to help establish what functional role these sites might possess. The proposed work is based on the hypothesis that a study of the structure- activity relationships (SAR) of benzomorphan analogs will provide important information about: (1) the structural requirements for binding to the sigma-1 and sigma-2 sites; (2) the nature of the sigma-1 and sigma-2 pharmacophore; and (3) agonist-antagonist interactions and toxicity in relation to the sigma subtypes. The specific aims are to design and synthesize benzomorphan analogs for use in determining the sigma-1 and sigma-2 pharmacophore. Biological studies will include: (1) radioligand binding competitive experiments against [3H(+)-pentazocine, [3H]DTG, [3H]TCP, [3H]QNB, [3H]DAMGO, [3H]bremazocine, and [3H]sulpiride in the guinea pig or rat brain; and (2) pharmacological studies to evaluate behavioral effects following microinjection of sigma selective compounds into the substantia nigra of rats. The proposed in vitro studies will provide information on structural features required for selective binding to the sigma-1 and sigma-2 binding sites and on the biochemical properties of these sites. The in vivo studies will provide information on possible functional roles of these binding sites. In addition, this program of research may provide novel and selective biochemical tools that could be useful in neuroimaging studies and/or for the purification of sigma subtypes.